A randomized, placebo-controlled trial of abacavir intensification in HIV-1-infected adults with virologic suppression on a protease inhibitor-containing regimen

Scott M. Hammer, Heather Ribaudo, Roland Bassett, John W. Mellors, Lisa M. Demeter, Robert W. Coombs, Judith Currier, Gene D. Morse, John G. Gerber, Ana I. Martinez, William Spreen, Margaret A Fischl, Kathleen E. Squires

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background and Objective: Maximizing the durability of viral suppression is a key goal of antiretroviral therapy. The objective of AIDS Clinical Trials Group Study 372A was to determine whether the intensification strategy of adding abacavir to an effective indinavir-dual nucleoside regimen would delay the time to virologic failure. Methods: Zidovudine-experienced subjects (n=229) on therapy with indinavir + zidovudine + lamivudine with plasma HIV-1 RNA levels <500 copies/mL were randomized to abacavir 300 mg twice daily or placebo. The primary endpoint was the time to treatment failure, defined as a composite of confirmed virologic failure (2 consecutive HIV-1 RNAs >200 copies/mL) and treatment discontinuation. Results: At baseline, the study population was 88% male with a median age of 41 years and median CD4 cell count of 250/mm 3. Median follow-up was 4.4 years. The primary endpoint was reached in 61/116 of abacavir versus 62/113 of placebo recipients (P = .77); virologic failure occurred in 34/116 and 42/113 patients, respectively (P = .22). There were no differences in the proportions of subjects with plasma HIV-1 RNA levels below 50 copies/mL, in CD4 cell count increases, nor adverse events between the arms. In the study, 17% of subjects developed nephrolithiasis, 2% experienced abacavir hypersensitivity, and 4.8% experienced at least 1 serious cardiovascular event (7 [6%] in the abacavir arm, 4 [3.5%] in the placebo arm). In additional secondary and post hoc analyses, rates of intermittent viremia, suppression below a plasma HIV-1 RNA level of 6 copies/mL, and HIV-1 proviral DNA levels in peripheral blood mononuclear cells were not significantly different in the 2 arms. Conclusions: The strategy of intensification with abacavir in patients who are virologically suppressed on a stable antiretroviral regimen does not confer a clinical or virologic benefit. As antiretroviral regimens have become more potent since this trial was completed, it will be even more difficult to prove that late intensification of already virologically suppressed patients will add benefit. However, studies are warranted with drugs with new mechanisms of action to determine whether the level of persistent viremia below 50 copies/ mL can be further reduced and what influence this may have on latent HIV reservoirs.

Original languageEnglish
Pages (from-to)312-324
Number of pages13
JournalHIV Clinical Trials
Volume11
Issue number6
DOIs
StatePublished - Jan 1 2010

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Protease Inhibitors
HIV-1
Randomized Controlled Trials
Placebos
Indinavir
Zidovudine
Viremia
RNA
CD4 Lymphocyte Count
Lamivudine
Nucleosides
Blood Cells
Hypersensitivity
Acquired Immunodeficiency Syndrome
Therapeutics
abacavir
Clinical Trials
HIV
DNA
Pharmaceutical Preparations

Keywords

  • abacavir
  • antiretroviral therapy
  • intensification

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)

Cite this

A randomized, placebo-controlled trial of abacavir intensification in HIV-1-infected adults with virologic suppression on a protease inhibitor-containing regimen. / Hammer, Scott M.; Ribaudo, Heather; Bassett, Roland; Mellors, John W.; Demeter, Lisa M.; Coombs, Robert W.; Currier, Judith; Morse, Gene D.; Gerber, John G.; Martinez, Ana I.; Spreen, William; Fischl, Margaret A; Squires, Kathleen E.

In: HIV Clinical Trials, Vol. 11, No. 6, 01.01.2010, p. 312-324.

Research output: Contribution to journalArticle

Hammer, SM, Ribaudo, H, Bassett, R, Mellors, JW, Demeter, LM, Coombs, RW, Currier, J, Morse, GD, Gerber, JG, Martinez, AI, Spreen, W, Fischl, MA & Squires, KE 2010, 'A randomized, placebo-controlled trial of abacavir intensification in HIV-1-infected adults with virologic suppression on a protease inhibitor-containing regimen', HIV Clinical Trials, vol. 11, no. 6, pp. 312-324. https://doi.org/10.1310/hct1105-312
Hammer, Scott M. ; Ribaudo, Heather ; Bassett, Roland ; Mellors, John W. ; Demeter, Lisa M. ; Coombs, Robert W. ; Currier, Judith ; Morse, Gene D. ; Gerber, John G. ; Martinez, Ana I. ; Spreen, William ; Fischl, Margaret A ; Squires, Kathleen E. / A randomized, placebo-controlled trial of abacavir intensification in HIV-1-infected adults with virologic suppression on a protease inhibitor-containing regimen. In: HIV Clinical Trials. 2010 ; Vol. 11, No. 6. pp. 312-324.
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abstract = "Background and Objective: Maximizing the durability of viral suppression is a key goal of antiretroviral therapy. The objective of AIDS Clinical Trials Group Study 372A was to determine whether the intensification strategy of adding abacavir to an effective indinavir-dual nucleoside regimen would delay the time to virologic failure. Methods: Zidovudine-experienced subjects (n=229) on therapy with indinavir + zidovudine + lamivudine with plasma HIV-1 RNA levels <500 copies/mL were randomized to abacavir 300 mg twice daily or placebo. The primary endpoint was the time to treatment failure, defined as a composite of confirmed virologic failure (2 consecutive HIV-1 RNAs >200 copies/mL) and treatment discontinuation. Results: At baseline, the study population was 88{\%} male with a median age of 41 years and median CD4 cell count of 250/mm 3. Median follow-up was 4.4 years. The primary endpoint was reached in 61/116 of abacavir versus 62/113 of placebo recipients (P = .77); virologic failure occurred in 34/116 and 42/113 patients, respectively (P = .22). There were no differences in the proportions of subjects with plasma HIV-1 RNA levels below 50 copies/mL, in CD4 cell count increases, nor adverse events between the arms. In the study, 17{\%} of subjects developed nephrolithiasis, 2{\%} experienced abacavir hypersensitivity, and 4.8{\%} experienced at least 1 serious cardiovascular event (7 [6{\%}] in the abacavir arm, 4 [3.5{\%}] in the placebo arm). In additional secondary and post hoc analyses, rates of intermittent viremia, suppression below a plasma HIV-1 RNA level of 6 copies/mL, and HIV-1 proviral DNA levels in peripheral blood mononuclear cells were not significantly different in the 2 arms. Conclusions: The strategy of intensification with abacavir in patients who are virologically suppressed on a stable antiretroviral regimen does not confer a clinical or virologic benefit. As antiretroviral regimens have become more potent since this trial was completed, it will be even more difficult to prove that late intensification of already virologically suppressed patients will add benefit. However, studies are warranted with drugs with new mechanisms of action to determine whether the level of persistent viremia below 50 copies/ mL can be further reduced and what influence this may have on latent HIV reservoirs.",
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AU - Ribaudo, Heather

AU - Bassett, Roland

AU - Mellors, John W.

AU - Demeter, Lisa M.

AU - Coombs, Robert W.

AU - Currier, Judith

AU - Morse, Gene D.

AU - Gerber, John G.

AU - Martinez, Ana I.

AU - Spreen, William

AU - Fischl, Margaret A

AU - Squires, Kathleen E.

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N2 - Background and Objective: Maximizing the durability of viral suppression is a key goal of antiretroviral therapy. The objective of AIDS Clinical Trials Group Study 372A was to determine whether the intensification strategy of adding abacavir to an effective indinavir-dual nucleoside regimen would delay the time to virologic failure. Methods: Zidovudine-experienced subjects (n=229) on therapy with indinavir + zidovudine + lamivudine with plasma HIV-1 RNA levels <500 copies/mL were randomized to abacavir 300 mg twice daily or placebo. The primary endpoint was the time to treatment failure, defined as a composite of confirmed virologic failure (2 consecutive HIV-1 RNAs >200 copies/mL) and treatment discontinuation. Results: At baseline, the study population was 88% male with a median age of 41 years and median CD4 cell count of 250/mm 3. Median follow-up was 4.4 years. The primary endpoint was reached in 61/116 of abacavir versus 62/113 of placebo recipients (P = .77); virologic failure occurred in 34/116 and 42/113 patients, respectively (P = .22). There were no differences in the proportions of subjects with plasma HIV-1 RNA levels below 50 copies/mL, in CD4 cell count increases, nor adverse events between the arms. In the study, 17% of subjects developed nephrolithiasis, 2% experienced abacavir hypersensitivity, and 4.8% experienced at least 1 serious cardiovascular event (7 [6%] in the abacavir arm, 4 [3.5%] in the placebo arm). In additional secondary and post hoc analyses, rates of intermittent viremia, suppression below a plasma HIV-1 RNA level of 6 copies/mL, and HIV-1 proviral DNA levels in peripheral blood mononuclear cells were not significantly different in the 2 arms. Conclusions: The strategy of intensification with abacavir in patients who are virologically suppressed on a stable antiretroviral regimen does not confer a clinical or virologic benefit. As antiretroviral regimens have become more potent since this trial was completed, it will be even more difficult to prove that late intensification of already virologically suppressed patients will add benefit. However, studies are warranted with drugs with new mechanisms of action to determine whether the level of persistent viremia below 50 copies/ mL can be further reduced and what influence this may have on latent HIV reservoirs.

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